The severe impact of hypertension-induced heart disease (HHD, i.e. cardiac hypertrophy, heart failure) is underscored by the fact that about 30% of the US adult population has high blood pressure, and hypertension is associated with a 2-3 fold higher risk for developing heart failure. The prevalence of HHD also drastically increases with aging, which poses a growing HHD problem with the aging population in US. Hence finding effective treatments for HHD is of great clinical importance and urgency. Recently, we discovered that the onset of hypertension was associated with an immediate elevation of Ca2+/calmodulin-dependent kinase II (CaMKII) activity in the heart which preceded the development of cardiac hypertrophy and heart failure. Since CaMKII is known to play significant role in inducing hypertrophy and modulating excitation-contraction coupling, we hypothesize that hypertension causes elevation of CaMKII activity which, in turn, triggers the development of hypertrophy and heart failure. Conversely, CaMKII inhibition may have beneficial effects on mitigating the HHD development. We propose to test this hypothesis by using CaMKII inhibitor to treat the spontaneously hypertensive rat (SHR) in vivo at three distinct stages during HHD development: onset of hypertension, overt hypertrophy, and heart failure. Specific Aim-1 will establish the effects of CaMKII inhibitor treatment on the CaMKII4B and CaMKII4C isoform's activity at each HHD stage. Specific Aim-2 will examine the treatment effects on mitigating hypertrophy development and modulating heart function. Specific Aim-3 will systematically study the effects on CaMKII related Ca2+ handling proteins that control cardiac excitation-contraction. As the first step towards future translational research, we will also measure changes in CaMKII and its related Ca2+ handling molecules in human failing hearts. The similarities and differences between SHR and human failing hearts will be examined. The goal of this pilot study is to understand the effects of CaMKII4B and CaMKII4C on regulating the molecular changes that underlie the structural and functional remodeling during HHD development, and to investigate the potential of using CaMKII inhibition as a new therapeutic strategy for treating hypertension-induced hypertrophy, arrhythmias and heart failure. PUBLIC HEALTH RELEVANCE High blood pressure is a major risk factor for developing heart diseases. This project proposes to conduct a pilot study to explore the feasibility and the potential of inhibiting CaMKII in the heart as a new strategy for treating hypertensive heart disease. We will first conduct the pilot study using an animal model (spontaneously hypertensive rat) that mimics human clinical stages. The long term goal is to develop effective treatment for hypertension-induced hypertrophy, arrhythmias, and heart failure in human patients.